Abstract Background Among patients with non-ST-segment elevation myocardial infarction (NSTEMI) about 80% present with chest discomfort. Others have less obvious symptoms, but early diagnosis is crucial. Sex differences in symptoms have been reported to delay diagnosis in about half of women. This study aims to analyze the symptoms and its disparities caused by sex, age, comorbidities, and culprit lesion location. Methods Patients presenting with troponin elevation and at least one angiographically confirmed atherosclerotic lesion causing the myocardial ischemia (culprit lesion) between February 2018 and July 2023 were prospectively included in a single-center, all-comers, real-world registry. Results Information regarding symptoms was available for 842 NSTEMI patients with an identifiable culprit lesion. Chest discomfort was reported by 684 patients (81.2%), dyspnea by 361 (42.9%) with it being the primary symptom in 102 (12.1%), and atypical symptoms by 317 (37.6%) with it being the primary symptom in 56 (6.7%). Concretely, dizziness or syncope was reported by 82 patients (9.7%), nausea, vomiting or any other gastrointestinal symptoms by 73 (8.7%), epigastric, shoulder, arm, back, neck or jaw pain by 57 (6.8%), diaphoresis by 66 (7.8%), other vegetative symptoms like palpitations or anxiety by 56 (6.7%), fatigue by 37 (4.4%), and neurologic symptoms like sensory or motor impairments by 28 (3.3%). In women, the primary complaint was less often chest discomfort (76.3 vs. 82.9%, p=0.040), more often atypical symptoms (9.8 vs. 5.6%, p=0.049) and equally often dyspnea (14.0 vs. 11.5%, p=0.403). Gastrointestinal symptoms were more often reported by women (13.5 vs. 7.0%, p=0.006). Elderly, i.e., age ≥80 years, reported chest discomfort less often (75.4 vs. 83.0%, p=0.023), dyspnea more often (19.5 vs. 9.9%, p<0.001) and atypical symptoms equally often (5.1 vs. 7.1%, p=0.418). Likewise, diabetic had chest discomfort less often (74.3 vs. 84.5%, p<0.001), dyspnea more often (18.2 vs. 9.2%, p<0.001), and atypical symptoms equally often (7.4 vs. 6.3%, p=0.633). No differences regarding primary symptoms were observed for dyslipidemia (82.1 vs. 78.9% for chest discomfort, 12.1 vs. 12.1% for dyspnea, 5.8 vs. 9.0% for atypical symptoms, p>0.05 for all) and obesity (84.5 vs. 81.2% for chest discomfort, 9.8 vs. 12.5% for dyspnea, 5.7 vs. 6.3% for atypical symptoms, p>0.05 for all). For LM culprit lesions, dyspnea was more often the primary symptom compared to LAD, LCX, and RCA culprit lesions (17.4% for LM vs. 13.6% for LAD, 5.7% for LCX, and 13.2% for RCA, p=0.023), while no differences were observed for chest pain (73.9% for LM, 80.6% for LAD, 86.1% for LCX, and 80.2% for RCA, p=0.235) and atypical symptoms (8.7% for LM, 5.9% for LAD, 8.1% for LCX, and 6.6% for RCA, p=0.758). Conclusions Chest discomfort is significantly less often the primary symptom of NSTEMI in women, elderly and diabetic making these groups more vulnerable for delayed diagnosis or misdiagnosis.